Tissue-specific regulation of BMP signaling by -glycanase 1.

Mutations in the human glycanase 1 () cause a rare, multisystem congenital disorder with global developmental delay. However, the mechanisms by which and its homologs regulate embryonic development are not known. Here we show that encodes an -glycanase and exhibits a high degree of functional conservation with human NGLY1. Loss of results in developmental midgut defects reminiscent of midgut-specific loss of BMP signaling. mutant larvae also exhibit a severe midgut clearance defect, which cannot be fully explained by impaired BMP signaling. Genetic experiments indicate that Pngl is primarily required in the mesoderm during development. Loss of Pngl results in a severe decrease in the level of Dpp homodimers and abolishes BMP autoregulation in the visceral mesoderm mediated by Dpp and Tkv homodimers. Thus, our studies uncover a novel mechanism for the tissue-specific regulation of an evolutionarily conserved signaling pathway by an -glycanase enzyme.